Mast cell activation can occur in response to a variety of immunologic and non-immunologic stimuli. However, mast cell function is also subject to regulation by inhibitory receptors that transduce intracellular signals via associated tyrosine phosphatases, SHP-1 and/or SHP-2, and the inositol 5-phosphatase SHIP. Recent studies have demonstrated an important role for SHIP in regulating antigen receptor signaling in lymphoid and myeloid cells. In addition, SHIP is critical for preventing mast cell activation in the absence of antigen. It is presently unknown how SHIP is recruited into sites where it mediates this regulatory function. In preliminary studies, we have identified four novel SHIP- binding membrane glycoproteins in mast cells. We hypothesize that one or more of these glycoproteins may function as inhibitory molecules in the regulation of mast cell function. Furthermore, based on recent studies in B cells, we hypothesize that these and previously defined inhibitory molecules regulate mast cell function via association with SHIP and its effector p62dok. The specific aims of this proposal are to 1) identify novel inhibitory molecules that mediate SHIP activation in mast cells, and 2) define the role of SHIP and p62dok in regulating mast cell function.